It is recognized generally that certain small-granule cells occur in the epithelium of the mammalian respiratory tract. Their salient ultrastructural feature consists of numerous 1000 A membrane-bounded cytoplasmic granules with an intensely osmiophilic core; they incorporate exogenous L-DOPA and convert it to a fluorogenic monoamine. In this, they resemble catecholamine-containing, polypeptide hormone-producing cells implicated in neural and endocrine regulatory mechanisms in the gut, pancreas, thyroid gland and other organs. The supposition that they produce biologically active amines and polypeptides has far reaching implications for understanding the regulation of physical and metabolic pulmonary activities. However, their mere presence in the lung gives little clue to their true functions: (1) Polypeptide hormones act at varying distances from their sites of origin, (2) Our preliminary experiments point to the existence of two or more distinct classes of granulated cells in the respiratory tract of a given species, and (3) The relationship of these cells with the autonomic nervous system, of major value in assessing their physiological import, as yet is virtually undefined. We propose, by light and electron microscopy, enzymic histochemistry and monoamine fluorescence methods, to examine systematically these cells in the respiratory tract of the bat, rat, mouse and rabbit, focusing on (1) the distribution of granulated cells along the airway, (2) the distinction of possible subclasses of these cells, and (3) their physical and spatial relationships with other epithelial elements, the microvasculature, lymphatics and autonomic nervous system. Innervation patterns will be studied using pharmacological depletion of catecholamines, retrograde filling of nerve terminals with peroxidase marker and surgical denervation of the respiratory tract. We also hope to trace the differentiation of these cells within the developing lungs and at a later time to apply immunocytochemistry to granulated cells in the mature lung to try to localize some of the more ubiquitous of the polypeptide hormones (e.g., ACTH, calcitonin, somatostatin).